Circulation Research. 2000;86:829-833
(Circulation Research. 2000;86:829.)
© 2000 American Heart Association, Inc.
Gene Therapy for Restenosis
Melina R. Kibbe,
Timothy R. Billiar,
Edith Tzeng
From the Department of Surgery, University of Pittsburgh, Pittsburgh, Pa.
Correspondence to Melina R. Kibbe, MD, University of Pittsburgh, Department of Surgery, 677 Scaife Hall, Pittsburgh, PA 15261. E-mail kibbemr{at}msx.upmc.edu
Key Words: gene therapy gene transfer restenosis adenovirus
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Introduction
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Atherosclerosis is one of the leading causes of major
morbidity
and mortality in the United States. Arterial
insufficiency resulting
from flow-limiting lesions can lead to
myocardial, renal, mesenteric,
and extremity dysfunction. Treatments
for these atherosclerotic
arterial lesions include
arterial bypass and angioplasty. These
therapies are
limited by the development of intimal hyperplasia
(IH), thus reducing
hemodynamic improvement significantly. A
number of
pharmacological agents with antiplatelet and anticoagulant
properties
have failed to reduce the incidence and rate of
restenosis.
Because of the magnitude of the patient population
affected
by IH, there has been a tremendous need to develop a therapy
that
will successfully reduce its incidence. Over the last decade,
the
field of vascular gene therapy has emerged as a viable therapeutic
approach,
permitting the targeting of genes to produce local and
transient
effects on the development of IH. This review will discuss
the
rationale and preliminary data for the different genes that
have
been evaluated to date.
 |
Cytotoxic Gene Therapy
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One of the first reports of successful gene transfer to
vascular
cells was by Nabel et al in 1989.
1 These
investigators transfected
porcine endothelial cells ex
vivo with a retrovirus encoding
the ß-galactosidase gene and
reintroduced the cells onto
the denuded iliofemoral artery of a
syngeneic animal. The arterial
segments isolated 2 to 4
weeks later demonstrated endothelial
cells that
expressed the ß-galactosidase gene, thus indicating
successful
incorporation of the transgene into the transduced
cells. Landmark
follow-up experiments in which herpes simplex
virus thymidine kinase
(HSV-tk) was delivered to injured porcine
iliac
2 or rat
carotid
3 arteries using an adenoviral vector
were
published 5 years later (see Table online; http://www.circresaha.org).
This
approach, which is based on the conversion of coadministered
ganciclovir
to a toxic metabolite by HSV-tk, decreased the
neointima by
86% in the porcine model
2 and
46% in the rodent model.
3 Similarly,
gene transfer of
another cytotoxic gene product, cytosine deaminase,
which
converts 5-fluorocytosine to a powerful antimetabolite
5-fluorouracil,
has also been proven effective at reducing IH in a
rabbit model
of vascular injury.
4 These reports indicated
that gene therapy
to the vasculature was not only feasible but could
dramatically
inhibit IH and opened the door for additional vascular
gene
therapy investigation.
Studies of the effects of gene transfer after balloon injury in
nondiseased animal vessels are not representative of
human arterial disease, which is commonly the consequence
of atherosclerosis. Thus, evaluation of the injury
process in atherosclerotic animal vessels is important and can yield
pertinent information that may be more directly comparable to clinical
scenarios. Using an atherosclerotic rabbit model, Steg et
al5 delivered an adenoviral vector carrying the HSV-tk
gene to injured vessels and demonstrated a 42% reduction in
intima-to-media ratio (I/M) at 4 weeks after injury. Similarly,
Simari et al6 reported a 35% to 49% reduction in the
intimal area at 3 weeks but only a 21% reduction in I/M in an
atherosclerotic rabbit model of arterial injury. Although
these studies are preliminary, they do strongly suggest that cytotoxic
vascular gene therapy could also be effective in underlying
atherosclerotic disease.
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Cell Cycle Regulators
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Cellular proliferation is dependent on progression through
the
cell cycle that in turn is regulated by cyclins, cyclin-dependent
kinases
(cdks), and cdk inhibitors. The interaction of
cyclins and cdks
leads to their activation through sequential
phosphorylation,
and this activated complex can
phosphorylate retinoblastoma
protein (Rb). In its active
form, Rb is normally bound to DNA
elongation factor (E2F) and inhibits
DNA transcription. Phosphorylated
or
inactivated Rb releases E2F, DNA transcription is
initiated,
and cell cycle progression occurs. This process can be
inhibited
by naturally occurring cdk inhibitors that bind
to and inactivate
cyclins, cdks, or the cyclin-cdk
complex.
7 Hence, interruptions
or alterations of any of
these cell cycle pathways can in theory
affect overall
neointima formation.
In 1995, a cDNA encoding a mutated form of Rb that cannot be
phosphorylated and hence remains active was developed.
Transfer of the mutant form of Rb into injured rodent and porcine
arteries in vivo reduced I/M by 42% and 47%,
respectively.8 Simple overexpression of a wild-type
phosphorylatable Rb was also able to inhibit smooth muscle cell (SMC)
proliferation, indicating that excess Rb is sufficient to inhibit cell
cycle progression.9 Additionally, different members of the
Rb family of proteins, namely pRb2/p130, have been delivered to the
vasculature and demonstrated efficacy in decreasing
neointima formation in a rodent model of vascular
injury.10
Later in 1995, Chang et al11 infected injured rat
carotid arteries with an adenoviral vector carrying the cdk
inhibitor p21, a member of the KIP/CIP family.
Overexpression of p21 reduced I/M by 46% at 20 days after injury. In
vitro analysis demonstrated that p21 elicited this
antiproliferative effect by inducing a G0/G1 cell cycle arrest in
vascular SMCs. The capacity of p21 gene transfer to inhibit IH has been
confirmed by additional studies in both rat and pig
arterial injury models.12 13 More recently,
Luo et al14 used titers of adenoviral p21 as low as
1x108 plaque-forming units (pfu) per artery to
reduce neointima formation by 58% in a rodent model.
Another member of the KIP/CIP family of cdk inhibitors is
p27, which is expressed constitutively in most cells. Overexpression of
p27 in rat carotid arteries also decreased I/M by 49%.15
Thus, interruption of the cell cycle through the overexpression of
endogenous cell cycle inhibitors holds promise
to limit IH through the inhibition of SMC proliferation.
After sustaining cellular injury and DNA damage, the tumor
suppressor p53 is induced and functions to arrest cell cycle
progression during DNA repair or activate apoptotic
pathways if the damage is too severe. These properties of p53 make it
an attractive candidate gene for vascular gene therapy. Yonemitsu et
al16 showed that hemagglutinating virus of Japan
(HVJ)mediated delivery of p53 to balloon-injured rabbit carotid
arteries markedly decreased intimal thickness.
Histological examination of these p53-treated vessels
demonstrated inhibition of cellular proliferation as well as impairment
of SMC differentiation. Furthermore, Scheinman et al17
showed that adenoviral delivery of wild-type p53 to injured rat carotid
arteries resulted in a dose-dependent reduction in
neointima formation by 47%, 51%, and 96% with escalating
doses of adenoviral vector administered (8x109,
1.6x1010, and 8x1010
pfu/mL, respectively).
The use of antisense oligonucleotides (ASOs) to
block critical pathways involved in cell cycle progression and cellular
proliferation has flourished in the past decade. Successful targets
have included c-myb, c-myc, PCNA, cdc2, and cdk2.7
Although many investigators have influenced the development of IH, one
study deserves mention. Shi et al18 delivered c-myc ASO to
porcine coronary arteries at the site of injury for only 22
seconds, yet a 70% reduction in the neointimal area was
observed compared with controls. This demonstrates that nonviral
methods of gene delivery, which may be safer and induce less of a host
immune response, can be quite efficacious.
 |
Intracellular Signal Transducers
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In mammalian cells, H-ras and the Raf serine/threonine
kinase
family of proteins are key signal transduction molecules. They
convey
mitogenic signals initiated by both receptor-ligand
interactions
at the cell surface and nonreceptor tyrosine kinases to
the
nucleus and upregulate certain nuclear transcription events
that
are directly linked to cellular proliferation.
19 By
blocking
early signal transduction, such as at the level of H-ras or
Raf
kinase, downstream signaling events and proliferation may also
be
arrested. Cioffi et al
20 used A-Raf and C-Raf ASO to
inhibit
vascular SMC proliferation in vitro. Ueno et al
21
created a
dominant-negative mutant of H-ras in which residue 57 was
altered
from aspartic acid to tyrosine. This mutation resulted in
inactivation
of wild-type H-ras. Adenoviral delivery of this
dominant-negative
H-ras to injured rat carotid arteries reduced IH by
81%. Another
approach focused on inhibiting mitogen-activated
protein kinase
signaling pathways by G proteins. A
G
ß
-binding peptide
that binds and depletes
the G
ß
that is necessary for intracellular
signaling
was overexpressed in rat carotid arteries using adenoviral
gene
delivery and led to a 70% reduction in neointima
size.
22 All
of these studies suggest that impairing signal
transduction
may be an efficient method of reducing the proliferative
response
to mitogens released after vascular injury. However, these
signals
are also central to events essential for cell survival, and
additional
studies are necessary to evaluate the potential detrimental
effects
of blocking signal transduction.
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Transcription Factors
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The rationale for targeting transcription factors with gene
therapy
is that these factors are upregulated by mitogenic
stimuli to
initiate a proliferative response, initiate new protein
synthesis,
or terminate cell cycle arrest. One such transcription
factor
commonly activated by mitogens is nuclear factor-

B
(NF-

B), which
is a cytoplasmic transcription factor involved in the
upregulation
of cytokines, adhesion molecules, and vasoactive
regulators.
The NF-

B complex is composed of several protein
subunits, including
p50 and p65. Autieri et al
23
suppressed NF-

B in SMCs in vitro
with ASO to p65 and observed a 63%
inhibition of proliferation
and a reduction in SMC adherence.
Administration of p65 ASO
in vivo in rat carotid arteries resulted in a
70% reduction
in neointima formation after balloon
injury.
Morishita et al24 described a novel approach to
vascular gene therapy in which a synthetic double-stranded DNA molecule
with high binding affinity for E2F was delivered to injured rat carotid
arteries using HVJ liposomes. This synthetic DNA behaves as a decoy
that binds and inactivates E2F, resulting in inhibition of
SMC proliferation. In rat carotid arteries, the administration of this
decoy DNA resulted in a 74% reduction in I/M.24
Therefore, by simply preventing E2F from binding to promoter regions of
genes involved with cellular proliferation, a significant effect on the
development of intimal thickness was observed.
Growth arrest homeobox (gax) is a transcription factor that
regulates cell cycle regulatory gene expression in response to mitogen
activation. Gax is expressed in quiescent SMCs in vitro but is
downregulated when the cells are stimulated with serum. Because gax
expression is associated with an antiproliferative phenotype in
SMCs, it was reasoned that gax overexpression might inhibit IH. Smith
et al25 reported that adenoviral delivery of gax to
injured rat carotid arteries reduced I/M by 69%. These data were
confirmed by Maillard et al,26 who demonstrated a 69%
reduction of I/M in rabbit iliac arteries. Another transcription factor
with activity similar to gax is GATA-6. Adenoviral gene transfer of
GATA-6 also inhibited IH by 50% in a rodent model.27
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Cytokines and Growth Factors
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The first cytokine administered in an animal model
to inhibit
IH was ß-interferon. Stephan et al
28
demonstrated that
adenoviral gene transfer of ß-interferon in a
porcine
model of arterial injury reduced
neointimal thickness by 23%
at 21 days after injury. This
inhibition of IH was not through
cell cycle arrest but through a
different mechanism.
Vascular endothelial growth factor (VEGF) is a
potent endothelium-specific angiogenic factor. With
this property, VEGF may assist in promoting
reendothelialization of denuded arterial
wall and therefore arrest IH sooner by halting the
mitogenic signals that originate at sites of platelet
and leukocyte attachment. Recombinant VEGF has been administered in a
rat model of arterial injury. VEGF-treated vessels were
80% reendothelialized by 2 weeks and nearly 100%
reendothelialized by 4 weeks versus 44% and 76% in
the control vessels, respectively.29 Measurements of I/M
revealed a 34% reduction in IH in VEGF-treated animals. Similarly,
rabbits subjected to femoral artery injury followed by stenting and
treatment with VEGF165 plasmid had accelerated
reendothelialization, reduced mural thrombus formation,
and decreased neointima formation.29
Basic fibroblast growth factor (bFGF) and platelet-derived
growth factor (PDGF) are two of the most important growth factors
involved in the vascular injury healing response. bFGF is released from
injured SMCs and initiates SMC proliferation and is a potent
endothelial mitogen. PDGF is a weaker SMC mitogen,
functioning predominantly as a chemotactic agent.7 Thus,
it is reasonable to conclude that inhibiting these growth factors may
affect neointima formation. Hanna et al30
delivered antisense bFGF using an adenoviral vector to rat carotid
arteries and reported a dose-dependent inhibition of I/M ranging from
29% to 86% with escalating concentrations of virus. PDGF-ß subunit
ASO produced a similar inhibition of IH.31 More recently,
Deguchi et al32 used adenoviral gene delivery to transfer
the extracellular region of the PDGF-ß receptor that binds to
PDGF-ß chains and acts as an antagonist to injured rat
arteries and also showed a significant reduction in IH. Thus, from the
above studies, it is apparent that by targeting different signaling
aspects of the vascular injury response, the overall development of IH
can be affected in a favorable manner.
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Nitric Oxide
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Endothelial cells are a source of regulatory
molecules that
are vitally important to vascular homeostasis, one of
which
is nitric oxide (NO). NO is synthesized by an
endothelial NO
synthase (eNOS) but can be produced in
much larger quantities
by an inducible NO synthase
(iNOS).
33 NO in the vasculature
is primarily
vasoprotective by inhibiting platelet and leukocyte
adhesion,
inhibiting SMC proliferation and migration, and promoting
endothelial
survival and proliferation.
7
At sites of vascular injury, the
endothelium is
disrupted and NO synthesis is impaired. Hence,
augmenting local NO
synthesis through gene therapy may help
arrest the proliferative
response to vascular injury. In 1995,
von der Leyen et
al
34 delivered eNOS to injured rat carotid
arteries using
HVJ liposomes and demonstrated a 70% reduction
in I/M. Chen et
al
35 seeded SMCs engineered to express eNOS
using
retroviruses onto injured rat carotid arteries and inhibited
neointima
formation by 37%.Others have similarly shown
that adenoviral
delivery of eNOS to injured rodent and porcine arteries
can
limit IH.
36 37
On an equimolar basis, iNOS produces much greater levels of NO
compared with eNOS.33 Additionally, in contrast to eNOS,
iNOS produces NO in a calcium-independent and sustained
manner.33 This property makes iNOS attractive because one
of the limiting factors in gene therapy is gene transfer efficiency.
Shears et al38 demonstrated that adenoviral-mediated iNOS
gene transfer to rat carotid arteries using
100- to 1000-fold lower
virus concentrations than most other vascular gene therapy studies
inhibited IH by 97%. In a porcine model of iliac artery injury, iNOS
gene transfer reduced IH by 52%, again using much less virus (3- to
20-fold less) than other vascular gene delivery
studies.38
 |
Fas Ligand
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Fas ligand (FasL) is an inducer of apoptosis in
certain cell
types. Hence, it is reasonable to hypothesize that
overexpression
of FasL in the vessel wall after injury may prevent IH.
Luo
et al
14 demonstrated that adenoviral gene transfer of
FasL
effectively inhibited IH. They then evaluated preimmunization
of
animals with the adenovirus to study the effect on
neointima
formation. In preimmunized animals, subsequent
infection with
a control adenoviral vector or Adp21 resulted in an
intense
T-cell infiltrate in the blood vessel wall, whereas subsequent
infection
with AdFasL resulted in minimal T-cell activation and a
reduction
in neointima formation.
14 Hence,
this protection from the adenoviral
preexposureinduced immune
response seemed unique to FasL.
This MiniReview is part of a thematic series on
Cardiovascular Gene Therapy, which includes the following
articles: Prospects for Gene Therapy for Heart
Failure
Gene Therapy for Restenosis
Human Gene Therapy: The Good, the Bad, and the Ugly
Vectors for Gene Therapy Gene Therapy for
Coagulation Disorders Gene Therapy for Hypertension
Charles Lowenstein, Toren Finkel, Eduardo Marbán,
Editors
Conclusion
There still remains a vast amount of knowledge to be
gathered about the events that occur after vascular injury that
contribute to IH. Over the last decade, and especially the last 5
years, vascular gene therapy has proven to be a potentially viable
option for preventing neointima formation and warrants
additional investigation. Additional investigations will determine if
any or all of these gene therapies will still be effective in
atherosclerotic arteries where the biology of healing may be more
complex.
Received December 30, 1999;
accepted March 3, 2000.
 |
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